PATHOPHYSIOLOGY OFTHE THYROID AND

PARATHYROID GLANDS

MUDr. Pavel Maruna

Thyroid gland

Physiology

Derived from embryonic thyroglossal duct2 lobes connected by an isthmus20 g weightThe only significant source of T4, ( T3 ... peripheral

conversion)T3, T4: 3-, 4- iodine-derivates of tyrosine

T3 is more potent metabolic factor than T4

Regulation of secretion:TRH - TSH - T4 axis

Thyroid gland

Physiology

Physiology

Total T4 (75-170 nmol / L, 80 - 90 g/den), total T3

Free T4 (fT4) 11 - 22 pmol / L, free T3

TSH (0,5-6,5 mU / L)

USG, Color DopplerScintigraphy (131I, 132I, 99mTc) - differ. dg. of hot / cold nodi,

ectopic goiter, metastases

FNAB (Fine Needle Aspiration Biopsy)

Examination methods

Auto-Ab in diagnostics

(high specificity)

auto-Ab anti-TSH-R binding to different epitops: growth, goiter stimulation ... Graves-Basedow dis. inhibition ... hypothyroid idiopatic

myxoedemaauto-Ab anti-microsomal = anti-TPO (thyroid peroxidase)

... Hashimoto dis.auto-Ab anti-Tg (thyroglobulin) ... x pathogeneticauto-Ab anti-T3... in 40% autoimmmune thyroiditis

Examination methods

USG: Normal thyroid gland

MRI: Nodular goiter

Color USG: Blood flow

Examination methods

131I scintigraphy:Retrosternal goiter

Examination methods

131I scintigraphy:Thyroid cancer - „cold“ nodule

Examination methods

Biopsy (FNAB)

Examination methods

Micro follicular/solid thyroid nodule

Thyroid gland

Pathology

Primary disorders (thyroid gland)Secondary disorders (pituitary gland)Receptor disorders

Thyroid gland

Physiological effects:

• Essential in fetal development• Heat production• Metabolic activity level (activity of cellular Na/K ATP-ase)• Glucose metabolism (uptake of glucose in GIT)• Cholesterol• Haemopoiesis• Bone formation

Thyroid gland

Pathological manifestation

1. Functionalhypothyroidismhyperthyroidism

2. Localgoitermechanic syndrome (dyspnoe, dysfagia, vessels)

3. Systemic (non-endocrine)metastases

EtiologyEtiology

FunctionFunction

Local signsLocal signs

Chronic lymfocytic thyroiditisGraves Basedow dis....

NormalHypothyroidismHyperthyroidism

GoiterMechanic syndrome (dyspnoe, dysfagia, vessel compression

Thyroid gland

Eufunctional goiter

= Goiter with normal hormonal production, x tumor or inflammation

Usually asymptomatic, event. dysfagia, dyspnoe.

High incidence in last decades x iodine prophylaxis and nutritional status

Etiology• iodine insuf. (endemic goiter)• strumigens in food, drugs (SFA, TBCstatics, Li,

resorcinol)• malnutrition• hereditary factors• juvenile goiter (?)• iodine overload (Wolf-Chaikoff effect) - risk of

lymphocyte thyroitidis

Thyroid tumors

Carcinoma malignant lymphoma, sarcoma, carcino / sarcoma, adenoma

2-4x incidence in female

0,5-1,0 % of all carcinomas, increasing incidence !

Risk factors:• ion. irradiation (papillary ca)• high TSH (papillary ca, follicular ca)x relations to jódu

Histological types:

• Papillary (60-70 %) - differentiated, low risk, but possible change to anaplastic form

• Follicular (15-30 %)- " -• Anaplastic – x differentiated, high malignant• Medullary (from C cells)

Thyroid tumors

Thyroid tumors

Clinical coursesolitary note, slow growth, local pain (invasive growth),dysphagia, dyspnoelymph node metastasesdistant metastases

(lungs, path. fractures..)

131I scintigraphy:metastases of papillary ca

Thyroid tumors

Examination methods

USGGammagraphy – usually „cold node" (x iodine accumulation)FNAB (fine needle aspiration biopsy) - cytologyAlternatively: biopsy with Vim-Silverman needle - histology

LaboratoryEuthyroid status calcitonin, PCT, CEA … medullary ca Tg, anti-Tg … non-medullary ca, using for post-surgical

monitoring

Thyroid tumors

Prognosis:Relatively good, better in younger patients, differ. forms

Thyroid tumors

Chronic lymphocytis thyreoiditis

Classification (Volfé)

• Hashimoto dis. (= with goiter)• autoimmune thyr. in children and adults• chronic fibrotic variant• atrophic variant• primary myxedema• Riedl goiter = rare inflamm. form

Autoimmune dis. (primary defect of TS lymphocytes ?)auto-Ab anti-Tgauto-Ab anti-microsomal… and also other auto-Ab

Etiology:

Genetic dispositionsFamily history is positive in 50% !HLA-DR5 variant with goiterHLA-B8, DR3 atrophic variant (see DM type I)HLA-DR2 lower risk30% Turner sy … LTfrequent combination with other autoimmune dis.:

LT in 65% patients with DM type IPOEMS sy

= polyneuropathy, organomegaly, endocrinopathy,

M protein, skin changes

polyglandular sy I, II, III (thyrogastric sy)

Chronic lymphocytis thyreoiditis

Pathogenesis:

Stimuli - may provoke manifestation of latent LT

iodine (cave amiodarone) Liafter delivery - LT in 10% females (usually transient, but 25%

hypothyroidism)cytokine treatment (IFNα, IL-2, GM-CSF) 10% T4

(TPO inhibition, role of NK Ly dysfunction (T4)

Chronic lymphocytis thyreoiditis

Prevalence

In non-selected necropsies: 40-45% fem. and 20% malesFemales 7:1 males, mean age of manifestation 59 yr.

Precancerosis? In thyr. lymphoma – prevalence of LT is 80x higher

Chronic lymphocytis thyreoiditis

Graves-Basedow dis.

Autoimmmune inflammationMost often cause of thyrotoxicosis

Auto-Ab (IgG) anti-TSH R(TRAK, TSI, LATS, LATS protectors)

TH LyThe role of provocative stress factors

(emotion, fever)

Graves-Basedow dis.

Clinical trias:goiter + exophthalmus + tachycardia(oligo- and monosymptomatic formsin old patients)

Hypothyroidism

Etiology

• Primary T4, T3, TSH• Secondary T4, T3, TSH• Congenital receptor deficiency - peripheral resistance to

the T4 action T4, T3, TSH

1. Immunopathology (lymphocytic thyroiditis - Hashimoto´s disease)

2. Iodine deficiency3. Subacute thyroiditis

Hypothyroidism

Manifestation:

• goiter (hyperplasia of thyroid gland - TSH growth stimulation)

• myxedema (forearm, ...)• bradypsychia, lethargy, inability to concentrate• anemia (impaired B12 vit. metabolism)• cardiovascular signs (bradycardia, ventricular dilation)• impaired renal function• neuromuscular system dysfunctions (paresthesia,

muscle weakness)

Congenital hypothyroidism

Hypothyroidism

= cretinism (infants) - mental dysfunction, cyanosis, poor feeding, retardation of bone maturation

Hypothyroidism

Laboratory findings

T4, free T4, T3 TSH cholesterolmacrocytic anemia

Hyperthyroidism

Etiology

primary T4, T3, TSHsecondary T4, T3, TSH (very rare !)

Graves disease (diffuse toxic goiter)autoimmune disorder, autoantibody against TSH-receptorsToxic adenoma (carcinoma) of thyroid glandHashimoto´s thyroiditis (early stage)

Hyperthyroidism

Manifestation

palpitation, hyperkinesia, excesive sweatingthyroid enlargement (goiter)ophthalmopathyupper lid retractionperiorbital edemaprotrusioncorneal involvementsight lossloss of muscle massdiarhheaaccelerated bone maturationdyspnoe

Hyperthyroidism

Laboratory findings

T4, free T4, T3 TSH cholesterol

Ca++

PTH

Glycoprotein, 115 AA precursor, intracel. storageProteolytic removal of N-termin. structure84 AA active hormone

Regulation of synthesis / secretion by ↓ plasma Ca2+

Negative feedback regulation

PTH receptors on plasma membraneAdenylat cyclase, cAMP action

Ca++

PTH

Effects:PTH / Ca2+ regulation Kidney: retention of Ca++ … tubular reabsorption of Ca and

MgBone: release of Ca++ from bone (osteoclastic x

osteoblastic differentiation and actionGIT (via vit. D) absorption of Ca++ from the gut

Ca++

PTH

Effects:

Ca++

Calcitonin (CT)

Product of parafollicular C cells of thyroid glandPeptide, 32 AA, Mv 3,7 kDPrecursor - procalcitonin (inflammatory marker)

Regulation: Stimulation by ↑ Ca2+

Effects:Ca2+ regulation (low importance in humans) Excess or deficiency has not dramatic clinical manifestationKidney: release of Ca2+

Bone: uptake of Ca2+

Ca++

Vitamin D

Vitamin D3 ... CholecalciferolVitamin D2 ... Ergocalciferol

Sterol hormones90 %synthesis in skin10 % food intake

Hydroxylation25-OH- D3 (liver)1,25-OH- D3 (kidney)

Ca++

Vitamin D

Effects:Increase of plasma Ca2+ and PO4 … conditions for bone

mineralizationGIT: facilitation of Ca2+ and PO4 absorptionBone: direct effect of ossification of osteoid tissueSkin: trophic effect (x alopecia)Other tissues: immunological effects

Ca++

Parathyroid glands

4 bodies near both upper and lower thyroid lobe0,05-0,30 g10 - 20 % atypical localization (mediastinum)

Hypoparathyroidism

Etiology:

• Postoperative (after TTE … transitory or irreversible)• Idiopathic … Autoimmune destruction of glands,

combination with Addison dis. + Hashimoto dis.• Congenital - inactive PTH production• Functional (↓↓Mg2+) … transitory

PseudohypoparathyroidismPTH receptor disease in kidneys / or postreceptor dis.... Negative feedback … ↑PTHmanifestation: short staue, obesitas, ↓IQ, brachydactyliaPseudo-pseudo-hypoparathyroidism? incomplete manifestation of pseudohypo-PTH

Hypoparathyroidism

Acute manifestation:

↓Ca2+ + ↑PO4 → neuromuscular hyperactivity

Manifestation depends on actual Ca2+ levelsParesthesia (tingling around mouth,

fingers)Hyperventilation (as alarm reaction) →

↓CO2 → alkalosis → Ca2+ binding to proteins

Tetany (attact begins with paresthesias … painful spasms of extremities and face … flexion of the wrist and MP joints, extension of IP joints

Adrenergic reaction (tachycardia, sweating)

Hypoparathyroidism

Chronic manifestation:“Latent tetany”

HeadacheEpileptic paroxysmsPosterior lenticular cataractECC changes (QT prolongation)Hypotension, cardiac failureDental manifestation (during childhood)Chvostek´s sign (tapping the facial nerve below the

zygomatic arch → twitching of the corner of the mouth and other facial muscles)

Trousseau´s sign (manometer cuff is inflated above systolic pressure for 2 min. → typical carpal spasm)

Hypoparathyroidism

Laboratory signs:

Plasma - Ca2+, urine Ca2+

Plasma - high PO4

Plasma - iPTH

Hypoparathyroidism

Differential diagnostics of tetany

Ca2+ (PTH, bowel resorption, renal loss)- alkalosis (e.g. hyperventilation) K+

Mg2+

- neurogenic (psychogenic) = constitutional spasmophilia

Hyperparathyroidism

Etiology

Primary - Adenoma (3/4, 5-10% atypical localization)HyperplasiaCarcinoma

Secondary - response to Ca2+ (renal failure, vitamin D, pseudohypo-PTH)

Tertiary - chronic stimulation - hyperplasia of parathyr. gland

Hyperparathyroidism

Manifestation

Most patients have no signs!

Laboratory findingsplasma Ca2+, urine Ca2+

plasma low PO4

tubular resorption 80%, clearence of PO4

iPTH urine cAMP ALP

Clinical syndroms

• Bone syndrome(depends on a primary diagnosis)

• Renal syndrome(polyuria, polydipsia, lithiasis, nefrocalcinosis)

• GIT syndrome(constipation, nausea, vomiting)

• Neuromuscular syndrome(muscular weakness, ECG - bradycardia, arrythmia)

• Neuropsychical syndrome(psychosis, somnolence, coma)

Hyperparathyroidism

Hyperparathyroidism

Manifestation

Bone syndromeosteoporosis (RTG, densitometry)diffuse bone painpathological fractureosteitis fibrosa cystica - epulis gigantocellularisLabor. markers: ALP, citrate, urine OH-proline

RTG of wrist

„Salt and peper“

scull

Increased parathyroid activity leading to characteristic

subperiosteal resorption

Hyperparathyroidism

The bone changes are partially reversibleThe same finger pre- and post-treatment for hyper-PTH. Images were taken 6 months apart.

Hyperparathyroidism

Hyperparathyroidism

Manifestation

Renal syndromeCa urolithiasisNephrocalcinosis (soft tissue calcification)Polyuria (water and osmotic diuresis)

GIT syndromeFunctional dyspeptic syndrome

(nausea, vomiting, constipation !)Peptic ulcer (gastrin)Chronic pancreatitis

Hyperparathyroidism

Manifestation

Cardiovascular changesBradycardiaArrhythmia, short QT intervalArterial hypertension

Neurological / neuropsychical syndromeApathyDepressionMyopathy

Hyperparathyroidism

Diagnostics:

Laboratory findings

USGScintigraphyMRI

99mTc-MIBI scintigraphy:Atypical PTH adenoma

PO4 1,25-0H-vit. D3

Ca

PTH

binding of serum Ca

decreased production by the proximal convoluted tubule

retention

renal loss gut uptake of

Ca

secondary hyperparatyreodidism

bone resorption, commonly from subperiosteal regions and tufts of the phalanges, proximal humerus, tibia and femur, and calvarium

Ca++

Differential diagnostics:• Primary hyperparathyreosis ( PTH, Ca2+, HPO4

2-)• Vit. D3 intoxication ( PTH, Ca2+, HPO4

2-)• Adrenal cortex insufficiency

(cortisol blocks bowel resorption of Ca2+)• Malignity (breast cancer, bronchogenic ca, myeloma)

(PTHrP, IL-6 or other cytokine production)• Immobilization• Sarcoidosis (production of 1,25-OH-D3 from macrophages)• Hyperthyroidism

Ca++

Ca++

Differential diagnostics:

• Hypoparathyreosis ( PTH, Ca2+, HPO42-)

• Vitamin D3 deficiency ( PTH, Ca2+, HPO42-)

• Pancreatitis

• Chronic kidney failure ( PTH, Ca2+)• Malnutrition ( PTH, Ca2+, Mg2+)

Ca++